The mammalian gut harbors a vast association of microorganisms that are critical for optimizing host fitness and health. The interaction of bacteria with their hosts is complex, and ranges from pathogenic to beneficial. Beneficial properties of the intestinal flora include the extraction of nutrients from the host diet, priming of the host immune system, and development of the gut. The fruit fly, Drosophila melanogaster, is a powerful system for identifying and studying the effect of genes on behavior, aging, and disease. The effects of bacterial colonization of the Drosophila gut parallel many of the observations made in higher organisms. We have identified a Drosophila mutant that exhibits defects in gut bacterial colonization. In the mentored phase of the award, we propose to characterize this mutant and develop the tools necessary for studying microorganisms harbored in the fruit fly. We will also use genetic screening to identify other mutants that affect bacterial/host interactions in Drosophila. The characterization of these genes and the determination of their mechanisms of action will continue into the independent phase of this award. Prof. Seymour Benzer and his laboratory, over the last 5 decades, have made significant impacts in the fields of genetics, memory, mating behavior, circadian rhythms, development and aging, and neurodegeneration, using the fruit fly, Drosophila, as a model system. The lab environment is highly suitable for the proposed work. Our research will provide new insights into the interaction of host animals with their gut flora. Optimizing microbial/host interactions will promote longevity and improve the quality of human life-features already suggested by the use of probiotics (the addition of beneficial bacteria to food). Additionally, our research may lead to new pharmaceutical targets or methods for preventing the use of insects as disease vectors by microorganisms.